Tje project consists of a series of clinical trials evaluating the clinical efficacy and safety of experimental therapeutic agents for the control of acute pain and perioperative apprehension in ambulatory patients undergoing minor surgical procedures. A recently completed study evaluated the interaction of proglumide, an antagonist of cholecystokinin, with morphine for postoperative pain. Current studies are evaluating SCH 34826, a novel agent which inhibits the breakdown of enkephalin in the central nervous system, and spiradoline, a novel analgesic which acts at the kappa opioid receptor. The surgical removal of impacted third molars serves as a model for minor surgical procedures with associated intraoperative and postoperative pain and perioperative apprehension. All studies are double-blind with randomly allocated, parallel treatment groups and multiple dependent measures of therapeutic efficacy and clinical safety. Administration of 0.05 mg of proglumide was demonstrated to significantly potentiate and prolong the analgesic efficacy of 4 mg of proglumide for postoperative pain while higher doses of proglumide were without effect. These data provide support for the use of proglumide for the potentiation of opioid analgesia but without the side effects associated with higher dose of an opioid. Preliminary results of the evaluation of spiradoline failed to demonstrate any significant analgesia following intramuscular administration in the gluteus. IM administration in the deltoid resulted in detectable analgesia and provides the rationale for continued study of this drug as a selective opioid analgesic. The evaluation of the enkephalinase inhibitor, SCH 34826, has not been completed. Demonstration of significant potentiation of morphine analgesia by proglumide may provide a rational basis for the pharmacologic management of pain without the limitations of higher doses of opioids. The preliminary results suggesting that spiradoline results in clinical analgesia provide a basis for continued investigation of experimental agents which act selectively through opioid receptor sub-types to determine if greater selectivity of analgesic action can be achieved. These strategies and the continuing evaluation of the enkephalinase inhibitor may provide support for therapeutic alternatives to traditional analgesic therapy.